The parietal cortex has a causal role in ambiguity computations in humans.

Humans often face the challenge of making decisions between ambiguous options. The level of ambiguity in decision-making has been linked to activity in the parietal cortex, but its exact computational role remains elusive. To test the hypothesis that the parietal cortex plays a causal role in computing ambiguous probabilities, we conducted consecutive fMRI and TMS-EEG studies. We found that participants assigned unknown probabilities to objective probabilities, elevating the uncertainty of their decisions. Parietal cortex activity correlated with the objective degree of ambiguity and with a process that underestimates the uncertainty during decision-making. Conversely, the midcingulate cortex (MCC) encodes prediction errors and increases its connectivity with the parietal cortex during outcome processing. Disruption of the parietal activity increased the uncertainty evaluation of the options, decreasing cingulate cortex oscillations during outcome evaluation and lateral frontal oscillations related to value ambiguous probability. These results provide evidence for a causal role of the parietal cortex in computing uncertainty during ambiguous decisions made by humans.

In vivo low-intensity magnetic pulses durably alter neocortical neuron excitability and spontaneous activity.

Magnetic brain stimulation is a promising treatment for neurological and psychiatric disorders. However, a better understanding of its effects at the individual neuron level is essential to improve its clinical application. We combined focal low-intensity repetitive transcranial magnetic stimulation (LI-rTMS) to the rat somatosensory cortex with intracellular recordings of subjacent pyramidal neurons in vivo. Continuous 10 Hz LI-rTMS reliably evoked firing at ∼4-5 Hz during the stimulation period and induced durable attenuation of synaptic activity and spontaneous firing in cortical neurons, through membrane hyperpolarization and a reduced intrinsic excitability. However, inducing firing in individual neurons by repeated intracellular current injection did not reproduce the effects of LI-rTMS on neuronal properties. These data provide a novel understanding of mechanisms underlying magnetic brain stimulation showing that, in addition to inducing biochemical plasticity, even weak magnetic fields can activate neurons and enduringly modulate their excitability. KEY POINTS: Repetitive transcranial magnetic stimulation (rTMS) is a promising technique to alleviate neurological and psychiatric disorders caused by alterations in cortical activity. Our knowledge of the cellular mechanisms underlying rTMS-based therapies remains limited. We combined in vivo focal application of low-intensity rTMS (LI-rTMS) to the rat somatosensory cortex with intracellular recordings of subjacent pyramidal neurons to characterize the effects of weak magnetic fields at single cell level. Ten minutes of LI-rTMS delivered at 10 Hz reliably evoked action potentials in cortical neurons during the stimulation period, and induced durable attenuation of their intrinsic excitability, synaptic activity and spontaneous firing. These results help us better understand the mechanisms of weak magnetic stimulation and should allow optimizing the effectiveness of stimulation protocols for clinical use.

Revisiting 'brain modes' in a new computational era: approaches for the characterization of brain-behavioural associations.

The study of brain-function relationships is undergoing a conceptual and methodological transformation due to the emergence of network neuroscience and the development of multivariate methods for lesion-deficit inferences. Anticipating this process, in 1998 Godefroy and co-workers conceptualized the potential of four elementary typologies of brain-behaviour relationships named 'brain modes' (unicity, equivalence, association, summation) as building blocks able to describe the association between intact or lesioned brain regions and cognitive processes or neurological deficits. In the light of new multivariate lesion inference and network approaches, we critically revisit and update the original theoretical notion of brain modes, and provide real-life clinical examples that support their existence. To improve the characterization of elementary units of brain-behavioural relationships further, we extend such conceptualization with a fifth brain mode (mutual inhibition/masking summation). We critically assess the ability of these five brain modes to account for any type of brain-function relationship, and discuss past versus future contributions in redefining the anatomical basis of human cognition. We also address the potential of brain modes for predicting the behavioural consequences of lesions and their future role in the design of cognitive neurorehabilitation therapies.

Patterns of axono-cortical evoked potentials: an electrophysiological signature unique to each white matter functional site?

BACKGROUND: Brain-to-brain evoked potentials constitute a new methodology that could help to understand the network-level correlates of electrical stimulation applied for brain mapping during tumor resection. In this paper, we aimed to describe the characteristics of axono-cortical evoked potentials recorded from distinct, but in the same patient, behaviorally eloquent white matter sites. METHODS: We report the intraoperative white matter mapping and axono-cortical evoked potentials recordings observed in a patient operated on under awake condition of a diffuse low-grade glioma in the left middle frontal gyrus. Out of the eight behaviorally eloquent sites identified with 60-Hz electrical stimulation, five were probed with single electrical pulses (delivered at 1 Hz), while recording evoked potentials on two electrodes, covering the inferior frontal gyrus and the precentral gyrus, respectively. Postoperative diffusion-weighted MRI was used to reconstruct the tractograms passing through each of the five stimulated sites. RESULTS: Each stimulated site generated an ACEP on at least one of the recorded electrode contacts. The whole pattern-i.e., the specific contacts with ACEPs and their waveform-was distinct for each of the five stimulated sites. CONCLUSIONS: We found that the patterns of ACEPs provided unique electrophysiological signatures for each of the five white matter functional sites. Our results could ultimately provide neurosurgeons with a new tool of intraoperative electrophysiologically based functional guidance.

Axono-cortical evoked potentials as a new method of IONM for preserving the motor control network: a first study in three cases.

BACKGROUND: White matter stimulation in an awake patient is currently the gold standard for identification of functional pathways. Despite the robustness and reproducibility of this method, very little is known about the electrophysiological mechanisms underlying the functional disruption. Axono-cortical evoked potentials (ACEPs) provide a reliable technique to explore these mechanisms. OBJECTIVE: To describe the shape and spatial patterns of ACEPs recorded when stimulating the white matter of the caudal part of the right superior frontal gyrus while recording in the precentral gyrus. METHODS: We report on three patients operated on under awake condition for a right superior frontal diffuse low-grade glioma. Functional sites were identified in the posterior wall of the cavity, whose 2-3-mA stimulation generated an arrest of movement. Once the resection was done, axono-cortical potentials were evoked: recording electrodes were put over the precentral gyrus, while stimulating at 1 Hz the white matter functional sites during 30-60 s. Unitary evoked potentials were averaged off-line. Waveform was visually analyzed, defining peaks and troughs, with quantitative measurements of their amplitudes and latencies. Spatial patterns of ACEPs were compared with patients' own and HCP-derived structural connectomics. RESULTS: Axono-cortical evoked potentials (ACEPs) were obtained and exhibited complex shapes and spatial patterns that correlated only partially with structural connectivity patterns. CONCLUSION: ACEPs is a new IONM methodology that could both contribute to elucidate the propagation of neuronal activity within a distributed network when stimulating white matter and provide a new technique for preserving motor control abilities during brain tumor resections.

Game theoretical mapping of white matter contributions to visuospatial attention in stroke patients with hemineglect.

White matter bundles linking gray matter nodes are key anatomical players to fully characterize associations between brain systems and cognitive functions. Here we used a multivariate lesion inference approach grounded in coalitional game theory (multiperturbation Shapley value analysis, MSA) to infer causal contributions of white matter bundles to visuospatial orienting of attention. Our work is based on the characterization of the lesion patterns of 25 right hemisphere stroke patients and the causal analysis of their impact on three neuropsychological tasks: line bisection, letter cancellation, and bells cancellation. We report that, out of the 11 white matter bundles included in our MSA coalitions, the optic radiations, the inferior fronto-occipital fasciculus and the anterior cingulum were the only tracts to display task-invariant contributions (positive, positive, and negative, respectively) to the tasks. We also report task-dependent influences for the branches of the superior longitudinal fasciculus and the posterior cingulum. By extending prior findings to white matter tracts linking key gray matter nodes, we further characterize from a network perspective the anatomical basis of visual and attentional orienting processes. The knowledge about interactions patterns mediated by white matter tracts linking cortical nodes of attention orienting networks, consolidated by further studies, may help develop and customize brain stimulation approaches for the rehabilitation of visuospatial neglect.

"I do not feel my hand where I see it": causal mapping of visuo-proprioceptive integration network in a surgical glioma patient.

A recent tasked-based fMRI study unveiled a network of areas implicated in the process of visuo-proprioceptive integration of the right hand. In this study, we report a case of a patient operated on in awake conditions for a glioblastoma of the left superior parietal lobule. When stimulating a white matter site in the anterior wall of the cavity, the patient spontaneously reported a discrepancy between the visual and proprioceptive perceptions of her right hand. Using several multimodal approaches (axono-cortical evoked potentials, tractography, resting-state functional connectivity), we demonstrated converging support for the hypothesis that tumor-induced plasticity redistributed the left-lateralized network of right-hand visuo-proprioceptive integration towards its right-lateralized homolog.

Pre-stimulus theta power is correlated with variation of motor evoked potential latency: a single-pulse TMS study.

There has been a growing interest in the role of pre-stimulus oscillations on cortical excitability in visual and motor systems. Prior studies focused on the relationship between pre-stimulus neuronal activity and TMS-evoked motor evoked potentials (MEPs) have reported heterogeneous results. We aimed to assess the role of pre-stimulus neural activity on the latency of MEPs, which might enhance our understanding of the variability of MEP signals, and potentially provide information on the role played by cortical activity fluctuations in the excitability of corticospinal pathways. Near-threshold single-pulse TMS (spTMS) was applied at random intervals over the primary motor cortex of 14 healthy participants while they sat passively, to trigger hand muscle contractions. Multichannel EEG was recorded during spTMS blocks. Spearman correlations between both the variation in MEP onset latencies and peak-to-peak MEP amplitudes, and the pre-stimulus power of EEG oscillations were calculated across participants. We found that the variation in MEP latency was positively correlated with pre-stimulus power in the theta range (4-7 Hz) in a broad time window (- 3.1 to - 1.9 s) preceding the spTMS generating the MEP. No correlation between pre-stimulus power in any frequency band and MEP amplitude was found. Our results show that pre-stimulus theta oscillations are correlated with the variation in MEP latency, an outcome measure determined by fiber conduction velocity and synaptic delays along the corticospinal tract. This finding could prove useful for clinicians using MEP latency-based information in pre- or intra-operative diagnostics of corticospinal impairment.

Game theoretical mapping of causal interactions underlying visuo-spatial attention in the human brain based on stroke lesions.

Anatomical studies conducted in neurological conditions have developed our understanding of the causal relationships between brain lesions and their clinical consequences. The analysis of lesion patterns extended across brain networks has been particularly useful in offering new insights on brain-behavior relationships. Here we applied multiperturbation Shapley value Analysis (MSA), a multivariate method based on coalitional game theory inferring causal regional contributions to specific behavioral outcomes from the characteristic functional deficits after stroke lesions. We established the causal patterns of contributions and interactions of nodes of the attentional orienting network on the basis of lesion and behavioral data from 25 right hemisphere stroke patients tested in visuo-spatial attention tasks. We calculated the percentage of damaged voxels for five right hemisphere cortical regions contributing to attentional orienting, involving seven specific Brodmann Areas (BA): Frontal Eye Fields, (FEF-BA6), Intraparietal Sulcus (IPS-BA7), Inferior Frontal Gyrus (IFG-BA44/BA45), Temporo-Parietal Junction (TPJ-BA39/BA40), and Inferior Occipital Gyrus (IOG-BA19). We computed the MSA contributions of these seven BAs to three behavioral clinical tests (line bisection, bells cancellation, and letter cancelation). Our analyses indicated IPS as the main contributor to the attentional orienting and also revealed synergistic influences among IPS, TPJ, and IOG (for bells cancellation and line bisection) and between TPJ and IFG (for bells and letter cancellation tasks). The findings demonstrate the ability of the MSA approach to infer plausible causal contributions of relevant right hemisphere sites in poststroke visuo-spatial attention and awareness disorders. Hum Brain Mapp 38:3454-3471, 2017. © 2017 Wiley Periodicals, Inc.

Direct current stimulation over the anterior temporal areas boosts semantic processing in primary progressive aphasia.

OBJECTIVE: Noninvasive brain stimulation in primary progressive aphasia (PPA) is a promising approach. Yet, applied to single cases or insufficiently controlled small-cohort studies, it has not clarified its therapeutic value. We here address the effectiveness of transcranial direct current stimulation (tDCS) on the semantic PPA variant (sv-PPA), applying a rigorous study design to a large, homogeneous sv-PPA cohort. METHODS: Using a double-blind, sham-controlled counterbalanced cross-over design, we applied three tDCS conditions targeting the temporal poles of 12 sv-PPA patients. Efficiency was assessed by a semantic matching task orthogonally manipulating "living"/"nonliving" categories and verbal/visual modalities. Conforming to predominantly left-lateralized damage in sv-PPA and accounts of interhemispheric inhibition, we applied left hemisphere anodal-excitatory and right hemisphere cathodal-inhibitory tDCS, compared to sham stimulation. RESULTS: Prestimulation data, compared to 15 healthy controls, showed that patients had semantic disorders predominating with living categories in the verbal modality. Stimulation selectively impacted these most impaired domains: Left-excitatory and right-inhibitory tDCS improved semantic accuracy in verbal modality, and right-inhibitory tDCS improved processing speed with living categories and accuracy and processing speed in the combined verbal × living condition. INTERPRETATION: Our findings demonstrate the efficiency of tDCS in sv-PPA by generating highly specific intrasemantic effects. They provide "proof of concept" for future applications of tDCS in therapeutic multiday regimes, potentially driving sustained improvement of semantic processing. Our data also support the hotly debated existence of a left temporal-pole network for verbal semantics selectively modulated through both left-excitatory and right-inhibitory brain stimulation. Ann Neurol 2016;80:693-707.

Visual Contrast Sensitivity Improvement by Right Frontal High-Beta Activity Is Mediated by Contrast Gain Mechanisms and Influenced by Fronto-Parietal White Matter Microstructure.

Behavioral and electrophysiological studies in humans and non-human primates have correlated frontal high-beta activity with the orienting of endogenous attention and shown the ability of the latter function to modulate visual performance. We here combined rhythmic transcranial magnetic stimulation (TMS) and diffusion imaging to study the relation between frontal oscillatory activity and visual performance, and we associated these phenomena to a specific set of white matter pathways that in humans subtend attentional processes. High-beta rhythmic activity on the right frontal eye field (FEF) was induced with TMS and its causal effects on a contrast sensitivity function were recorded to explore its ability to improve visual detection performance across different stimulus contrast levels. Our results show that frequency-specific activity patterns engaged in the right FEF have the ability to induce a leftward shift of the psychometric function. This increase in visual performance across different levels of stimulus contrast is likely mediated by a contrast gain mechanism. Interestingly, microstructural measures of white matter connectivity suggest a strong implication of right fronto-parietal connectivity linking the FEF and the intraparietal sulcus in propagating high-beta rhythmic signals across brain networks and subtending top-down frontal influences on visual performance.

Fronto-Parietal Anatomical Connections Influence the Modulation of Conscious Visual Perception by High-Beta Frontal Oscillatory Activity.

May white matter connectivity influence rhythmic brain activity underlying visual cognition? We here employed diffusion imaging to reconstruct the fronto-parietal white matter pathways in a group of healthy participants who displayed frequency-specific ameliorations of visual sensitivity during the entrainment of high-beta oscillatory activity by rhythmic transcranial magnetic stimulation over their right frontal eye field. Our analyses reveal a strong tract-specific association between the volume of the first branch of the superior longitudinal fasciculus and improvements of conscious visual detection driven by frontal beta oscillation patterns. These data indicate that the architecture of specific white matter pathways has the ability to influence the distributed effects of rhythmic spatio-temporal activity, and suggest a potentially relevant role for long-range connectivity in the synchronization of oscillatory patterns across fronto-parietal networks subtending the modulation of conscious visual perception.

Causal contributions of the left frontal eye field to conscious perception.

The quest for the neural correlates of consciousness has led to controversial results. When contrasting consciously seen versus unseen stimuli, some authors have proposed that consciousness is related to activity in visual areas along the ventral cortical visual stream, while others propose the implication of parietal and frontal regions ( Dehaene and Changeux 2011). When invisibility is caused by neglect or inattention, high levels of activity recorded in early visual areas ( Vuilleumier et al. 2001) suggest that further activity in fronto-parietal regions might be necessary for conscious perception. Recent functional magnetic resonance imaging evidence ( Chica, Paz-Alonso, et al. 2012) suggested a key role for the left frontal eye field (FEF) in the attentional modulation of visual consciousness. Here, we used the high temporal resolution and causal power of event-related transcranial magnetic stimulation to explore the causal contributions of the left FEF on conscious perception and to assess whether or not these effects are mediated by the orienting of spatial attention. Our results provide the first causal evidence on the contribution of the left FEF to conscious visual perception and indicate that such effects are likely to be mediated by its known role on attentional orienting.

Causal frequency-specific contributions of frontal spatiotemporal patterns induced by non-invasive neurostimulation to human visual performance.

Neural oscillatory activity is known to play a crucial role in brain function. In the particular domain of visual perception, specific frequency bands in different brain regions and networks, from sensory areas to large-scale frontoparietal systems, have been associated with distinct aspects of visual behavior. Nonetheless, their contributions to human visual cognition remain to be causally demonstrated. We hereby used non-uniform (and thus non-frequency-specific) and uniform (frequency-specific) high-beta and gamma patterns of noninvasive neurostimulation over the right frontal eye field (FEF) to isolate the behavioral effects of oscillation frequency and provide causal evidence that distinct visual behavioral outcomes could be modulated by frequency-specific activity emerging from a single cortical region. In a visual detection task using near-threshold targets, high-beta frequency enhanced perceptual sensitivity (d') without changing response criterion (beta), whereas gamma frequency shifted response criterion but showed no effects on perceptual sensitivity. The lack of behavioral modulations by non-frequency-specific patterns demonstrates that these behavioral effects were specifically driven by burst frequency. We hypothesize that such frequency-coded behavioral impact of oscillatory activity may reflect a general brain mechanism to multiplex functions within the same neural substrate. Furthermore, pathological conditions involving impaired cerebral oscillations could potentially benefit in the near future from the use of neurostimulation to restore the characteristic oscillatory patterns of healthy systems.

Impact of brain tissue filtering on neurostimulation fields: a modeling study.

Electrical neurostimulation techniques, such as deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS), are increasingly used in the neurosciences, e.g., for studying brain function, and for neurotherapeutics, e.g., for treating depression, epilepsy, and Parkinson's disease. The characterization of electrical properties of brain tissue has guided our fundamental understanding and application of these methods, from electrophysiologic theory to clinical dosing-metrics. Nonetheless, prior computational models have primarily relied on ex-vivo impedance measurements. We recorded the in-vivo impedances of brain tissues during neurosurgical procedures and used these results to construct MRI guided computational models of TMS and DBS neurostimulatory fields and conductance-based models of neurons exposed to stimulation. We demonstrated that tissues carry neurostimulation currents through frequency dependent resistive and capacitive properties not typically accounted for by past neurostimulation modeling work. We show that these fundamental brain tissue properties can have significant effects on the neurostimulatory-fields (capacitive and resistive current composition and spatial/temporal dynamics) and neural responses (stimulation threshold, ionic currents, and membrane dynamics). These findings highlight the importance of tissue impedance properties on neurostimulation and impact our understanding of the biological mechanisms and technological potential of neurostimulatory methods.

Causal evidence supporting functional dissociation of verbal and spatial working memory in the human dorsolateral prefrontal cortex.

The human dorsolateral prefrontal cortex (dlPFC) is crucial for monitoring and manipulating information in working memory, but whether such contributions are domain-specific remains unsettled. Neuroimaging studies have shown bilateral dlPFC activity associated with working memory independent of the stimulus domain, but the causality of this relationship cannot be inferred. Repetitive transcranial magnetic stimulation (rTMS) has the potential to test whether the left and right dlPFC contribute equally to verbal and spatial domains; however, this is the first study to investigate the interaction of task domain and hemisphere using offline rTMS to temporarily modulate dlPFC activity. In separate sessions, 20 healthy right-handed adults received 1 Hz rTMS to the left dlPFC and right dlPFC, plus the vertex as a control site. The working memory performance was assessed pre-rTMS and post-rTMS using both verbal-'letter' and spatial-'location' versions of the 3-back task. The response times were faster post-rTMS, independent of the task domain or stimulation condition, indicating the influence of practice or other nonspecific effects. For accuracy, rTMS of the right dlPFC, but not the left dlPFC or vertex, led to a transient dissociation, reducing spatial, but increasing verbal accuracy. A post-hoc correlation analysis found no relationship between these changes, indicating that the substrates underlying the verbal and spatial domains are functionally independent. Collapsing across time, there was a trend towards a double dissociation, suggesting a potential laterality in the functional organisation of verbal and spatial working memory. At a minimum, these findings provide human evidence for domain-specific contributions of the dlPFC to working memory and reinforce the potential of rTMS to ameliorate cognition.

Neural bases of the interactions between spatial attention and conscious perception.

Recent behavioral observations suggest that some forms of attentional orienting have the ability to modulate access to perceptual consciousness. However, the neural structures subserving such processes remain uncertain. We used functional magnetic resonance imaging during a visual discrimination task with near-threshold targets preceded by peripheral cues to identify the neural bases of the interactions between spatial attention and conscious visual perception. During the cue-target period critical for spatial orienting, regions within a frontoparietal network, including nodes of the dorsal attentional system, were more strongly engaged for consciously perceived targets than for nonperceived targets at attended locations. Moreover, activation increased for "unseen" targets in more ventral frontoparietal regions, known to be part of a system involved in attentional reorienting. Functional connectivity analyses revealed tighter coupling between frontoparietal nodes for valid cues leading to "seen" reports and for invalid cues leading to unseen reports. We conclude that spatial orienting to peripheral stimuli, subserved by frontoparietal attentional networks, plays a major role in determining the content of our conscious experience.

Fronto-tectal white matter connectivity mediates facilitatory effects of non-invasive neurostimulation on visual detection.

The causal ability of pre-target FEF activity to modulate visual detection for perithreshold stimuli has been recently demonstrated in humans by means of non-invasive neurostimulation. Yet in spite of the network-distributed effects of these type of techniques, the white matter (WM) tracts and distant visual nodes contributing to such behavioral impact remain unknown. We hereby used individual data from a group of healthy human subjects, who received time-locked pulses of active or sham Transcranial Magnetic Stimulation (TMS) to the right Frontal Eye Field (FEF) region, and experienced increases in visual detection sensitivity. We then studied the extent to which interindividual differences in visual modulation might be dependent on the WM patterns linking the targeted area to other regions relevant for visuo-attentional behaviors. We report a statistically significant correlation between the probability of connection in a right fronto-tectal pathway (FEF-Superior Colliculus) and the modulation of visual sensitivity during a detection task. Our findings support the potential contribution of this pathway and the superior colliculus in the mediation of visual performance from frontal regions in humans. Furthermore, we also show the ability of a TMS/DTI correlational approach to contribute to the disambiguation of the specific long-range pathways driving network-wide neurostimulatory effects on behavior, anticipating their future role in guiding a more efficient use of focal neurostimulation.

Benefit of multiple sessions of perilesional repetitive transcranial magnetic stimulation for an effective rehabilitation of visuospatial function.

Noninvasive neurostimulation techniques have been used alone or in conjunction with rehabilitation therapy to treat the neurological sequelae of brain damage with rather variable therapeutic outcomes. One potential factor limiting a consistent success for such techniques may be the limited number of sessions carried out in patients, despite reports that their accrual may play a key role in alleviating neurological deficits long-term. In this study, we tested the effects of seventy consecutive sessions of perilesional high-frequency (10 Hz) repetitive transcranial magnetic stimulation (rTMS) in the treatment of chronic neglect deficits in a well-established feline model of visuospatial neglect. Under identical rTMS parameters and visuospatial testing regimes, half of the subjects improved in visuospatial orienting performance. The other half experienced either none or extremely moderate ameliorations in the neglected hemispace and displayed transient patterns of maladaptive visuospatial behavior. Detailed analyses suggest that lesion location and extent did not account for the behavioral differences observed between these two groups of animals. We conclude that multi-session perilesional rTMS regimes have the potential to induce functional ameliorations following focal chronic brain injury, and that behavioral performance prior to the onset of the rTMS treatment is the factor that best predicts positive outcomes for noninvasive neurostimulation treatments in visuospatial neglect.